This proposal describes a 3-year career development plan for establishing the academic career of Principal Investigator, Dr. Jill Waalen, with a focus on the genetic epidemiology of osteoporosis. The project is designed to complement and build on the research skills and academic relationships Dr. Waalen has developed through post-graduate work to date. As a Research Associate at The Scripps Research Institute, Dr. Waalen has analyzed data from a pre-existing database of 41,000 subjects involved in a genetic study of hemochromatosis, a relatively rare, single gene disease. As a result of this work, she has published more than 17 articles in peer-reviewed journals! The project and career plan in this proposal will enable Dr. Waalen, who was recently promoted to the tenure-track position of Assistant Professor, 1) to develop an independent research program in genetic epidemiology with expertise in osteoporosis as a model of a common, multigenic disease, based on the recruitment of a new cohort of 10,000 subjects for genotyping studies which will provide the basis for other genetic epidemiology studies, both independently initiated and in collaboration with other researchers and 2) to receive direct mentoring in epidemiologic research to develop an academic base in epidemiology. The award will also enable her to pursue additional training in laboratory methods in genetic and genomic analysis and specialized statistical methods applicable to studying common, multigenic diseases. The specific project in the current proposal involves assessment of the association of single nucleotide polymorphisms of genes involved in the wnt/B-catenin pathway, including LDL-related receptor proteins (LRP)-5 and -6, with bone mineral density in 10,000 men and women age 65 and older recruited from the Kaiser-San Diego Health Appraisal Clinic who have undergone dual energy x- ray absorptiometry (DXA) scanning. The wnt/B-catenin pathway stimulates proliferation osteoblasts and has been implicated in determination of bone mineral density in animal and human studies. SNPs of other osteoporosis-related genes and interactions of SNPs in gene-gene interactions and with environmental factors will also be studied. As mentor for the career award, Dr. Ernest Beutler of The Scripps Research Institute (TSRI) will provide laboratory space and personnel for the large-scale genotyping required for the study and expertise in genetic analysis. As co-mentor for this project, Dr. Elizabeth Barrett-Connor will provide expertise in osteoporosis and guidance in epidemiologic methods and selection of bone-related candidate genes. Drs. James Koziol and Nicholas Schork of TSRI will provide additional expertise in statistical methods for analysis of multigenic diseases.